RNA m^(5)C修饰调控病毒复制的研究进展

Research advances in the role of RNA m^(5)C in viral replication

5-甲基胞嘧啶(5-methylcytosine,m^(5)C)作为一类重要的转录后修饰形式,在真核生物信使RNA(messenger RNA,mRNA)、转运RNA(transfer RNA,tRNA)和核糖体RNA(ribosomal RNA,rRNA)上普遍存在,并且参与调控RNA出核、翻译和稳定性维持等代谢加工过程.该修饰是动态可逆的,由甲基转移酶(methyltransferases)催化生成,并由去甲基化酶(demethylases)移除,通过招募特定的识别蛋白(reader proteins,readers)参与调控胚胎发育、肿瘤发展和干细胞分化等生理及病理过程.近期研究表明,除真核生物RNA外,病毒RNA上同样富含m^(5)C修饰,并且在转录、剪切和翻译等复制阶段扮演重要角色.此外,病毒感染可诱发宿主RNA的m^(5)C修饰改变,从而影响宿主对病毒感染的应答反应.随着RNA m^(5)C修饰测序技术的快速发展,病毒m^(5)C修饰的相关报道大量涌现,然而m^(5)C修饰在病毒感染中的具体调控机制至今尚未完全阐明.本文综述了近年来RNA m^(5)C修饰在逆转录病毒(retrovirus)、DNA病毒(DNA virus)、黄病毒(flavivirus)和冠状病毒(coronavirus)复制,以及宿主抗病毒免疫应答中的调控作用和分子机制,旨在为病毒表观遗传学研究提供参考.

It is well-known that RNA is the target of numerous chemical modifications which currently amount to over a hundred.Among them,5-methylcytosine(m^(5)C)is a prevalent RNA modification in multiple eukaryotic RNA species,such as messenger RNAs(mRNAs),transfer RNAs(tRNAs),ribosomal RNAs(rRNAs),vault RNAs(vtRNAs),long non-coding RNAs(lncRNAs)and enhancer RNAs(eRNAs).In recent years,several techniques for detecting m^(5)C have been developed,including UPLC-MS/MS,m^(5)C-MeRIP-seq,PA-m^(5)C-seq,RNA-BisSeq and nanopore sequencing.The rapid development of these high-throughput techniques sharply facilitates the in-depth studies of the biological functions of m^(5)C.The m^(5)C modification is enriched around start codon along mRNAs and conserved in tRNAs and rRNAs.It is a reversible RNA modification catalyzed by methyltransferases(NSUN,DNMT,and TRDMT family members)and removed by demethylases(TET family members and ALKBH1).The m^(5)C modification can be recognized by a set of RNA-binding proteins(YBX family members,ALYREF and FMRP)and is widely involved in the regulation of RNA metabolic processes,including nuclear export,stability and translation.In addition,the dysregulation of m^(5)C modification is closely related with the defect of DNA repair,cell proliferation,embryonic development and stem cell differentiation.Viruses are infectious agents that rely on host cells for replication.They have evolved numerous strategies to shape the cellular biosynthesis and metabolism machinery of hosts to complete their life cycle and propagate.One strategy is to modify viral RNAs using host m^(5)C RNA methyltransferases(NSUN1,NSUN2,NSUN5 and DNMT2),and thus directly regulates their transcription,splicing and translation.So far,combined with the high-throughput techniques,some viral m^(5)C landscapes have been precisely depicted,including human immunodeficiency virus type(HIV-1),murine leukemia virus(MLV),Epstein-Barr virus(EBV),and so on.Studies showed that the m^(5)C level of retroviral mRNAs is much higher than cellular mRNAs,suggesting this modification can be a special marker for host cells to distinguish“self”and“nonself”.In addition,the m^(5)C methylome of cellular RNAs is dynamically regulated under viral infection,leading to the suppression of host innate immunity.Therefore,it will be of great significance in the design and development of novel antiviral drugs by systemically understanding the molecular mechanisms of m^(5)C modification in controlling viral replication and host innate immunity.In this review,the latest findings of m^(5)C methyltransferases,demethylases,reader proteins and high-throughput sequencing techniques are presented.We discuss how m^(5)C modification is catalyzed and recognized on viral RNAs of retrovirus,DNA virus,flavivirus and coronavirus.Furthermore,we summarize the roles of RNA m^(5)C modification in viral replications and host innate immunity.This review will provide some valuable information for understanding the epigenetics in viral RNAs.